TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction
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TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. / Kjøbsted, Rasmus; Chadt, Alexandra; Jørgensen, Nicolas Oldenburg; Kido, Kohei; Larsen, Jeppe K; de Wendt, Christian; Al-Hasani, Hadi; Wojtaszewski, Jørgen.
In: Diabetes, Vol. 68, No. 9, 2019, p. 1756-1766.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction
AU - Kjøbsted, Rasmus
AU - Chadt, Alexandra
AU - Jørgensen, Nicolas Oldenburg
AU - Kido, Kohei
AU - Larsen, Jeppe K
AU - de Wendt, Christian
AU - Al-Hasani, Hadi
AU - Wojtaszewski, Jørgen
N1 - CURIS 2019 NEXS 278 © 2019 by the American Diabetes Association.
PY - 2019
Y1 - 2019
N2 - Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. Recently, we demonstrated that AMPK is necessary for AICAR, contraction and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine if TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately following contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle from wild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity following activation of the cellular energy sensor AMPK.
AB - Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. Recently, we demonstrated that AMPK is necessary for AICAR, contraction and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine if TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately following contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle from wild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity following activation of the cellular energy sensor AMPK.
KW - Faculty of Science
KW - AMPK
KW - Exercise
KW - Glucose uptake
KW - AS160
U2 - 10.2337/db18-0769
DO - 10.2337/db18-0769
M3 - Journal article
C2 - 31175100
VL - 68
SP - 1756
EP - 1766
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 9
ER -
ID: 222095228